Minimally Invasive Far Lateral Lumbar Discectomy With Modified Technique: Symptomatic Relief and Intersegmental Stability Study.

OBJECTIVE: To evaluate the use of a modified minimally invasive surgery (MIS) technique for far lateral lumbar discectomy (FLDH) that minimizes the degree of bony drilling required for nerve root decompression, increasing postoperative pain reduction rate with reduced risk of iatrogenic spinal instability. SUMMARY OF BACKGROUND DATA: FLDH accounts for approximately 10% of all lumbar disc herniations and is increasingly recognized in the era of advanced imaging techniques. These disc herniations typically result in extra-foraminal nerve root compression. Minimally invasive spine techniques are increasingly performed with various degrees of foraminal and facet removal to decompress the affected nerve root. METHODS: The study design involves a single institutional, retrospective cohort technical review. The review was completed of all patients undergoing MIS far lateral lumbar discectomy between 2010 and 2020. Cross-sectional, summary statistics were calculated for all variables. Counts and percentages were recorded for categorical variables and mean and standard deviations were calculated for continuous variables. RESULTS: A total of 48 patients underwent MIS far lateral lumbar discectomies (FLLD) from 2010 to 2020. The mean age was 63 ± 11.5 years (60.4% males), the mean BMI was 28.5 ± 5.5, and 20.8% smokers. The most common presenting complaint was both low back and radicular pain (79.2%) with 8.3% of patients suffering from motor weakness preoperatively. The mean follow-up time was 4.3 ± 2.7. The mean length of stay was 1.3 ± 1.4 days with 77.1% of patients discharged postoperative day one. Forty-three patients (93.5%) had improvement in their symptoms. Twenty-seven (58.7%) had complete resolution in 2.6 months on average. Six patients (13%) had immediate symptom resolution postoperatively. CONCLUSIONS: Our modified technique for FLLD allows MIS access to the extra-foraminal site of nerve root compression without the need for bony drilling. This minimizes postoperative pain and reduces the risk of iatrogenic spinal instability without sacrificing symptom resolution.

Fluoroscopy-based robotics in total hip arthroplasty mitigates laterality-based differences in acetabular cup placement when compared to the manual, fluoroscopic- assisted technique.

BACKGROUND: Robotic assistance in total hip arthroplasty (RA-THA) has been shown to minimize laterality-based differences in acetabular cup positioning. OBJECTIVE: To determine if the use of a novel, fluoroscopy-based RA-THA system mitigates differences in acetabular cup placement between left (L) and right (R) side hip procedures, when compared to manual, fluoroscopic-assisted technique. METHODS: We conducted a retrospective review of 106 consecutive mTHA (40 L/66 R) and 102 RA-THA (48 L/54 R) primary direct anterior approach procedures. All cases were performed by a single right-hand-dominant surgeon, for a pre-operative diagnosis of osteoarthritis, avascular necrosis, or rheumatoid arthritis. Outcomes included acetabular cup inclination and anteversion, and the proportion of cups within the Lewinnek safe-zone. RESULTS: The average inclination of mTHA L cases was smaller than that of mTHA R cases (41.10∘± 7.38 vs. 43.97∘± 6.27; p= 0.04). For RA-THA, L and R cup angles were similar. There were fewer overall mTHA hips within the Lewinnek safe-zone compared to RA-THA (0.59 vs. 0.78; p= 0.003), as well as fewer mTHA R cases than RA-THA R cases (0.59 vs. 0.80; p= 0.03) within safe zone. CONCLUSION: Use of a novel, fluoroscopy-based robotic system mitigates laterality-based differences in acetabular cup placement that were observed in a manual, fluoroscopic-assisted cohort.

Antibody specificity against highly conserved membrane protein Claudin 6 driven by single atomic contact point.

The tight junction protein claudin 6 (CLDN6) is differentially expressed on cancer cells with almost no expression in healthy tissue. However, achieving therapeutic MAb specificity for this 4 transmembrane protein is challenging because it is nearly identical to the widely expressed CLDN9, with only 3 extracellular amino acids different. Most other CLDN6 MAbs, including those in clinical development are cross-reactive with CLDN9, and several trials have now been stopped. Here we isolated rare MAbs that bind CLDN6 with up to picomolar affinity and display minimal cross-reactivity with CLDN9, 22 other CLDN family members, or across the human membrane proteome. Amino acid-level epitope mapping distinguished the binding sites of our MAbs from existing clinical-stage MAbs. Atomic-level epitope mapping identified the structural mechanism by which our MAbs differentiate CLDN6 and CLDN9 through steric hindrance at a single molecular contact point, the γ carbon on CLDN6 residue Q156.

A GPC2 antibody-drug conjugate is efficacious against neuroblastoma and small-cell lung cancer via binding a conformational epitope.

Glypican 2 (GPC2) is a MYCN-regulated, differentially expressed cell-surface oncoprotein and target for immune-based therapies in neuroblastoma. Here, we build on GPC2's immunotherapeutic attributes by finding that it is also a highly expressed, MYCN-driven oncoprotein on small-cell lung cancers (SCLCs), with significantly enriched expression in both the SCLC and neuroblastoma stem cell compartment.By solving the crystal structure of the D3-GPC2-Fab/GPC2 complex at 3.3 Å resolution, we further illustrate that the GPC2-directed antibody-drug conjugate (ADC; D3-GPC2-PBD), that links a human GPC2 antibody (D3) to DNA-damaging pyrrolobenzodiazepine (PBD) dimers, binds a tumor-specific, conformation-dependent epitope of the core GPC2 extracellular domain. We then show that this ADC induces durable neuroblastoma and SCLC tumor regression via induction of DNA damage, apoptosis, and bystander cell killing, notably with no signs of ADC-induced in vivo toxicity. These studies provide preclinical data to support the clinical translation of ADCs targeting GPC2.

Rare Ameloblastic Carcinoma Metastasis to the Cervical Spine: A Case Report.

BACKGROUND AND IMPORTANCE: Ameloblastic carcinoma (AC) is a malignant neoplasm of epithelial origin that typically arises from the mandible or maxilla. It represents approximately 2% of all odontogenic tumors. Gross total resection is the surgical goal given AC's aggressiveness and propensity for recurrence. We present the first reported AC metastasis to the cervical spine. CLINICAL PRESENTATION: A 61-yr-old African American female with a history of AC of bilateral mandibles and lung metastases presented with neck pain and right arm weakness progressive over several months. Cervical spine imaging demonstrated a cervical 3 pathological fracture with severe anterior vertebral body compression and resultant cervical 2-3 kyphotic deformity and bony retropulsion causing severe cord compression. The patient underwent a cervical 3 corpectomy and cervical 2-4 anterior fixation followed by a cervical 3 laminectomy and cervical 2-5 dorsal internal fixation and fusion. Postoperatively, the patient's neurological exam remained stable and imaging showed improved spinal alignment and appropriate anterior and posterior instrumentation. Unfortunately, the patient thereafter suffered a decline in performance status and progression of lung metastatic disease. Her oncology team is considering chemotherapy and stereotactic radiosurgery, but her prognosis remains grim. CONCLUSION: AC is a rare and aggressive pathology with a poor prognosis despite multimodal therapy. We present the first case of AC metastatic spread to the spine. We aim to bring this pathology to the attention of our worldwide neurosurgical colleagues and share our surgical approach and multidisciplinary management to assist those who may encounter this pathology in the future.

Management of a cervical spine neurenteric cyst via an anterior surgical approach: illustrative case.

BACKGROUND: Central nervous system neurenteric cysts (NCs) represent a rare entity thought to arise from failure of the separation of endodermal and neuroectodermal elements during week 3 of embryogenesis. They account for 0.7-1.3% of all spinal cord lesions and are typically intradural extramedullary lesions located near the cervicothoracic junction. Most NCs are associated with multisystem malformation disorders, making a solitary extramedullary NC a rare entity. OBSERVATIONS: A 45-year-old man presented with progressive right lower-extremity weakness and an inability to walk. Cervical spine magnetic resonance imaging demonstrated an approximately 1.6 × 1.1 × 2.7-cm, T2 hyperintense, nonenhancing, intradural, extramedullary cystic lesion at the level of C6-7 eccentric to the right with atrophy of the spinal cord. An anterior surgical approach was used for resection of the cyst in totality with C6-7 corpectomies and anterior plating and fixation from C5 to T1. Postoperatively at 1 month, the patient denied any significant neck or arm pain and demonstrated improving right lower-extremity strength, allowing some funcitonal independence. LESSONS: A solitary, extramedullary cervical NC is a rare entity, with a posterior surgical approach for resection primarily described in the literature. The authors present anterior corpectomy and plating with fixation as a viable surgical approach for this rare pathology.

Helix-Loop-Helix Factor Id3 (Inhibitor of Differentiation 3): A Novel Regulator of Hyaluronan-Mediated Adipose Tissue Inflammation.

OBJECTIVE: The aim of this study was to unravel mechanisms whereby deficiency of the transcription factor Id3 (inhibitor of differentiation 3) leads to metabolic dysfunction in visceral obesity. We investigated the impact of loss of Id3 on hyaluronic acid (HA) production by the 3 HAS isoenzymes (HA synthases; -1, -2, and -3) and on obesity-induced adipose tissue (AT) accumulation of proinflammatory B cells. Approach and Results: Male Id3-/- mice and respective wild-type littermate controls were fed a 60% high-fat diet for 4 weeks. An increase in inflammatory B2 cells was detected in Id3-/- epididymal AT. HA accumulated in epididymal AT of high-fat diet-fed Id3-/- mice and circulating levels of HA were elevated. Has2 mRNA expression was increased in epididymal AT of Id3-/- mice. Luciferase promoter assays showed that Id3 suppressed Has2 promoter activity, while loss of Id3 stimulated Has2 promoter activity. Functionally, HA strongly promoted B2 cell adhesion in the AT and on cultured vascular smooth muscle cells of Id3-/- mice, an effect sensitive to hyaluronidase. CONCLUSIONS: Our data demonstrate that loss of Id3 increases Has2 expression in the epididymal AT, thereby promoting HA accumulation. In turn, elevated HA content promotes HA-dependent binding of B2 cells and an increase in the B2 cells in the AT, which contributes to AT inflammation.

Experimental tasks of behavioral risk taking in alcohol administration studies: A systematic review.

Research on emerging adults shows this population exhibits the highest rates of alcohol use and engages in the riskiest of behaviors (Boyer, 2006; Fromme, Corbin, & Kruse, 2008). Among experimental paradigms, prior reviews have established an increase in behavioral risk taking while under the influence of alcohol (Moskowitz & Robinson, 1988; Martin et al., 2013; Weafer & Fillmore, 2016). Previous research highlighted the importance of alcohol dose on behavioral risk taking and the lack of agreement on which psychometric tools are most accurate in assessing behavioral risk taking (Beulow & Blaine, 2015; King, Toule, De Wit, & Holdstock, 2002). This systematic review of experimental paradigms assessing the effects of the dose of alcohol on various behavioral risk taking tasks suggest that higher alcohol doses (0.6 g/kg and above) produces the most robust increase in behavioral risk taking across tasks, compared to lower doses of alcohol (<0.6 g/kg). Results suggest the BART is the most sensitive behavioral risk task used to detect increases in risk taking in moderate/higher doses compared to lower doses of alcohol. This review also highlights the difficulty in measuring behavioral risk taking, as behavioral risk taking is a complex, multifaceted phenomenon that may involve multiple constructs and means to capture it. Future research is needed to standardize experimental administration protocols, to aid in advancing the field of alcohol administration experiments, and to determine the most accurate measurement of behavioral risk taking. PUBLIC HEALTH SIGNIFICANCE: Past experimental paradigms measuring behavioral risk taking under the influence of alcohol in emerging adults have used various alcohol administration paradigms, experimental protocols, and behavioral risk tasks. Key to examining behavioral risk taking via experimental paradigms should use at higher alcohol doses. Future interventions need to assess for levels of blood alcohol concentration when assessing for at-risk populations for alchol use disorders.

Hepatocyte-Specific Ablation or Whole-Body Inhibition of Xanthine Oxidoreductase in Mice Corrects Obesity-Induced Systemic Hyperuricemia Without Improving Metabolic Abnormalities.

Systemic hyperuricemia (HyUA) in obesity/type 2 diabetes facilitated by elevated activity of xanthine oxidoreductase (XOR), which is the sole source of uric acid (UA) in mammals, has been proposed to contribute to the pathogenesis of insulin resistance/dyslipidemia in obesity. Here, the effects of hepatocyte-specific ablation of Xdh, the gene encoding XOR (HXO), and whole-body pharmacologic inhibition of XOR (febuxostat) on obesity-induced insulin resistance/dyslipidemia were assessed. Deletion of hepatocyte Xdh substantially lowered liver and plasma UA concentration. When exposed to an obesogenic diet, HXO and control floxed (FLX) mice became equally obese, but systemic HyUA was absent in HXO mice. Despite this, obese HXO mice became as insulin resistant and dyslipidemic as obese FLX mice. Similarly, febuxostat dramatically lowered plasma and tissue UA and XOR activity in obese wild-type mice without altering obesity-associated insulin resistance/dyslipidemia. These data demonstrate that hepatocyte XOR activity is a critical determinant of systemic UA homeostasis, that deletion of hepatocyte Xdh is sufficient to prevent systemic HyUA of obesity, and that neither prevention nor correction of HyUA improves insulin resistance/dyslipidemia in obesity. Thus, systemic HyUA, although clearly a biomarker of the metabolic abnormalities of obesity, does not appear to be causative.

The protein acetylase GCN5L1 modulates hepatic fatty acid oxidation activity via acetylation of the mitochondrial ß-oxidation enzyme HADHA.

Sirtuin 3 (SIRT3) deacetylates and activates several mitochondrial fatty acid oxidation enzymes in the liver. Here, we investigated whether the protein acetylase GCN5 general control of amino acid synthesis 5-like 1 (GCN5L1), previously shown to oppose SIRT3 activity, is involved in the regulation of hepatic fatty acid oxidation. We show that GCN5L1 abundance is significantly up-regulated in response to an acute high-fat diet (HFD). Transgenic GCN5L1 overexpression in the mouse liver increased protein acetylation levels, and proteomic detection of specific lysine residues identified numerous sites that are co-regulated by GCN5L1 and SIRT3. We analyzed several fatty acid oxidation proteins identified by the proteomic screen and found that hyperacetylation of hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit α (HADHA) correlates with increased GCN5L1 levels. Stable GCN5L1 knockdown in HepG2 cells reduced HADHA acetylation and increased activities of fatty acid oxidation enzymes. Mice with a liver-specific deletion of GCN5L1 were protected from hepatic lipid accumulation following a chronic HFD and did not exhibit hyperacetylation of HADHA compared with WT controls. Finally, we found that GCN5L1-knockout mice lack HADHA that is hyperacetylated at three specific lysine residues (Lys-350, Lys-383, and Lys-406) and that acetylation at these sites is significantly associated with increased HADHA activity. We conclude that GCN5L1-mediated regulation of mitochondrial protein acetylation plays a role in hepatic metabolic homeostasis.

Adipose tissue-derived free fatty acids initiate myeloid cell accumulation in mouse liver in states of lipid oversupply.

Accumulation of myeloid cells in the liver, notably dendritic cells (DCs) and monocytes/macrophages (MCs), is a major component of the metainflammation of obesity. However, the mechanism(s) stimulating hepatic DC/MC infiltration remain ill defined. Herein, we addressed the hypothesis that adipose tissue (AT) free fatty acids (FFAs) play a central role in the initiation of hepatic DC/MC accumulation, using a number of mouse models of altered FFA supply to the liver. In two models of acute FFA elevation (lipid infusion and fasting) hepatic DC/MC and triglycerides (TGs) but not AT DC/MC were increased without altering plasma cytokines (PCs; TNFα and monocyte chemoattractant protein 1) and with variable effects on oxidative stress (OxS) markers. However, fasting in mice with profoundly reduced AT lipolysis (AT-specific deletion of adipose TG lipase; AAKO) failed to elevate liver DC/MC, TG, or PC, but liver OxS increased. Livers of obese AAKO mice that are known to be resistant to steatosis were similarly protected from inflammation. In high-fat feeding studies of 1, 3, 6, or 20-wk duration, liver DC/MC accumulation dissociated from PC and OxS but tracked with liver TGs. Furthermore, decreasing OxS by ~80% in obese mice failed to decrease liver DC/MC. Therefore, FFA and more specifically AT-derived FFA stimulate hepatic DC/MC accumulation, thus recapitulating the pathology of the obese liver. In a number of cases the effects of FFA can be dissociated from OxS and PC but match well with liver TG, a marker of FFA oversupply.

Preference for tap, bottled, and recycled water: Relations to PTC taste sensitivity and personality.

This study investigated people's preferences for different water sources and factors that predict such preferences using a blind taste test. Water preferences of 143 participants for one name-brand bottled water, one groundwater-sourced tap water, and one indirect potable reuse (IDR) water were assessed. For predictors of water preference, we measured each participant's PTC taste sensitivity and assessed two personality traits (Neuroticism, Openness to Experience). We also explored participants' descriptions of each water source. Results indicate a preference for water treated with Reverse Osmosis (RO) (bottled and IDR water) over groundwater-sourced water, which had higher pH levels and lower concentrations of Ca and HCO3-. PTC taste sensitivity did not predict preferences, while Openness to Experience and Neuroticism predicted preference for IDR water. Positive relations between Openness to Experience and preferences for bottled and IDR water were moderated by gender and were stronger among females. Participants described water primarily by its taste and texture. Findings suggest that (1) tap water treated by RO is equally preferable to some bottled water, (2) personality traits may affect water preferences, and (3) prior findings of gender differences in preferences for bottled water may reflect personality characteristics. Efforts to increase acceptance for sustainable water alternatives, such as IDR, may be more successful by assuring consumers about taste and addressing personality traits that encourage or inhibit use.

Reduced intestinal lipid absorption and body weight-independent improvements in insulin sensitivity in high-fat diet-fed Park2 knockout mice.

Mitochondrial dysfunction is associated with many human diseases and results from mismatch of damage and repair over the life of the organelle. PARK2 is a ubiquitin E3 ligase that regulates mitophagy, a repair mechanism that selectively degrades damaged mitochondria. Deletion of PARK2 in multiple in vivo models results in susceptibility to stress-induced mitochondrial and cellular dysfunction. Surprisingly, Park2 knockout (KO) mice are protected from nutritional stress and do not develop obesity, hepatic steatosis or insulin resistance when fed a high-fat diet (HFD). However, these phenomena are casually related and the physiological basis for this phenotype is unknown. We therefore undertook a series of acute HFD studies to more completely understand the physiology of Park2 KO during nutritional stress. We find that intestinal lipid absorption is impaired in Park2 KO mice as evidenced by increased fecal lipids and reduced plasma triglycerides after intragastric fat challenge. Park2 KO mice developed hepatic steatosis in response to intravenous lipid infusion as well as during incubation of primary hepatocytes with fatty acids, suggesting that hepatic protection from nutritional stress was secondary to changes in energy balance due to altered intestinal triglyceride absorption. Park2 KO mice showed reduced adiposity after 1-wk HFD, as well as improved hepatic and peripheral insulin sensitivity. These studies suggest that changes in intestinal lipid absorption may play a primary role in protection from nutritional stress in Park2 KO mice by preventing HFD-induced weight gain and highlight the need for tissue-specific models to address the role of PARK2 during metabolic stress.

Protective Role for B-1b B Cells and IgM in Obesity-Associated Inflammation, Glucose Intolerance, and Insulin Resistance.

OBJECTIVE: Little is known about the role(s) B cells play in obesity-induced metabolic dysfunction. This study used a mouse with B-cell-specific deletion of Id3 (Id3(Bcell KO)) to identify B-cell functions involved in the metabolic consequences of obesity. APPROACH AND RESULTS: Diet-induced obese Id3(Bcell KO) mice demonstrated attenuated inflammation and insulin resistance in visceral adipose tissue (VAT), and improved systemic glucose tolerance. VAT in Id3(Bcell KO) mice had increased B-1b B cells and elevated IgM natural antibodies to oxidation-specific epitopes. B-1b B cells reduced cytokine production in VAT M1 macrophages, and adoptively transferred B-1b B cells trafficked to VAT and produced natural antibodies for the duration of 13-week studies. B-1b B cells null for Id3 demonstrated increased proliferation, established larger populations in Rag1(-/-) VAT, and attenuated diet-induced glucose intolerance and VAT insulin resistance in Rag1(-/-) hosts. However, transfer of B-1b B cells unable to secrete IgM had no effect on glucose tolerance. In an obese human population, results provided the first evidence that B-1 cells are enriched in human VAT and IgM antibodies to oxidation-specific epitopes inversely correlated with inflammation and insulin resistance. CONCLUSIONS: NAb-producing B-1b B cells are increased in Id3(Bcell KO) mice and attenuate adipose tissue inflammation and glucose intolerance in diet-induced obese mice. Additional findings are the first to identify VAT as a reservoir for human B-1 cells and to link anti-inflammatory IgM antibodies with reduced inflammation and improved metabolic phenotype in obese humans.

Adipocyte progenitor cells initiate monocyte chemoattractant protein-1-mediated macrophage accumulation in visceral adipose tissue.

OBJECTIVE: Macrophages are important producers of obesity-induced MCP-1; however, initial obesity-induced increases in MCP-1 production precede M1 macrophage accumulation in visceral adipose tissue (VAT). The initial cellular source of obesity-induced MCP-1 in vivo is currently unknown. Preliminary reports based on in vitro studies of preadipocyte cell lines and adherent stroma-vascular fraction cells suggest that resident stromal cells express MCP-1. In the past several years, elegant methods of identifying adipocyte progenitor cells (AdPCs) have become available, making it possible to study these cells in vivo. We have previously published that global deletion of transcription factor Inhibitor of Differentiation 3 (Id3) attenuates high fat diet-induced obesity, but it is unclear if Id3 plays a role in diet-induced MCP-1 production. We sought to determine the initial cellular source of MCP-1 and identify molecular regulators mediating MCP-1 production. METHODS: Id3 (+/+) and Id3 (-/-) mice were fed either a standard chow or HFD for varying lengths of time. Flow cytometry, semi-quantitative real-time PCR, ELISAs and adoptive transfers were used to assess the importance of AdPCs during diet-induced obesity. Flow cytometry was also performed on a cohort of 14 patients undergoing bariatric surgery. RESULTS: Flow cytometry identified committed CD45(-)CD31 (-) Ter119(-)CD29(+)CD34(+)Sca-1(+)CD24(-) adipocyte progenitor cells as producers of high levels of MCP-1 in VAT. High-fat diet increased AdPC numbers, an effect dependent on Id3. Loss of Id3 increased p21(Cip1) levels and attenuated AdPC proliferation, resulting in reduced MCP-1 and M1 macrophage accumulation in VAT, compared to Id3 (+/+) littermate controls. AdPC rescue by adoptive transfer of 50,000 Id3 (+/+) AdPCs into Id3 (-/-) recipient mice increased MCP-1 levels and M1 macrophage number in VAT. Additionally, flow cytometry identified MCP-1-producing CD45(-)CD31(-)CD34(+)CD44(+)CD90(+) AdPCs in human omental and subcutaneous adipose tissue, with a higher percentage in omental adipose. Furthermore, high surface expression of CD44 marked abundant MCP-1 producers, only in visceral adipose tissue. CONCLUSIONS: This study provides the first in vivo evidence, to our knowledge, that committed AdPCs in VAT are the initial source of obesity-induced MCP-1 and identifies the helix-loop-helix transcription factor Id3 as a critical regulator of p21(Cip1) expression, AdPC proliferation, MCP-1 expression and M1 macrophage accumulation in VAT. Inhibition of Id3 and AdPC expansion, as well as CD44 expression in human AdPCs, may serve as unique therapeutic targets for the regulation of adipose tissue inflammation.

B2 cells suppress experimental abdominal aortic aneurysms.

Recent reports of rupture in patients with abdominal aortic aneurysm (AAA) receiving B-cell depletion therapy highlight the importance of understanding the role of B cells (B1 and B2 subsets) in the development of AAA. We hypothesized that B2 cells aggravate experimental aneurysm formation. The IHC staining revealed infiltration of B cells in the aorta of wild-type (C57BL/6) mice at day 7 after elastase perfusion and persisted through day 21. Quantification of immune cell types using flow cytometry at day 14 showed significantly greater infiltration of mononuclear cells, including B cells (B2: 93% of total B cells) and T cells in elastase-perfused aortas compared with saline-perfused or normal aortas. muMT (mature B-cell deficient) mice were prone to AAA formation similar to wild-type mice in two different experimental AAA models. Contradicting our hypothesis, adoptive transfer of B2 cells suppressed AAA formation (102.0% ± 7.3% versus 75.2% ± 5.5%; P < 0.05) with concomitant increase in the splenic regulatory T cell (0.24% ± 0.03% versus 0.92% ± 0.23%; P < 0.05) and decrease in aortic infiltration of mononuclear cells. Our data suggest that B2 cells constitute the largest population of B cells in experimental AAA. Furthermore, B2 cells, in the absence of other B-cell subsets, increase splenic regulatory T-cell population and suppress AAA formation.

Helix-loop-helix factor inhibitor of differentiation 3 regulates interleukin-5 expression and B-1a B cell proliferation.

OBJECTIVE: Natural immunity is emerging as an important mediator of protection from atherogenesis. Natural IgM antibodies that recognize oxidation-specific epitopes on low-density lipoprotein or phospholipids and the B-1a B cells that produce them attenuate atherosclerosis. We previously demonstrated that Apoe(-/-) mice globally deficient in the helix-loop-helix protein inhibitor of differentiation 3 (Id3) develop early diet-induced atherosclerosis. Furthermore, B cell-mediated attenuation of atherosclerosis in B cell-deficient mice was dependent on Id3. Here, we sought to determine whether Id3 regulates B-1a B cells and the natural antibodies that they produce and identify mechanisms mediating these effects. APPROACH AND RESULTS: Mice lacking Id3 had significantly fewer B-1a B cells in the spleen and peritoneal cavity and reduced serum levels of the natural antibody E06. B cell-specific deletion of Id3 revealed that this effect was not because of the loss of Id3 in B cells. Interleukin (IL)-33 induced abundant, Id3-dependent IL-5 production in the recently identified innate lymphoid cell, the natural helper (NH) cell, but not Th2 or mast cells. In addition, delivery of IL-5 to Id3-deficient mice restored B-1a B cell proliferation. B-1a B cells were present in aortic samples also containing NH cells. Aortic NH cells produced IL-5, a B-1a B cell mitogen in response to IL-33 stimulation. CONCLUSIONS: These studies are the first to identify NH and B-1a B cells in the aorta and provide evidence that Id3 is a key regulator of NH cell IL-5 production and B-1a B cell homeostasis.

Inhibitor of differentiation-3 mediates high fat diet-induced visceral fat expansion.

OBJECTIVE: Inhibitor of differentiation-3 (Id3) has been implicated in promoting angiogenesis, a key determinant of high-fat diet (HFD)-induced visceral adiposity. Yet the role of Id3 in HFD-induced angiogenesis and visceral adipose expansion is unknown. METHODS AND RESULTS: Id3(-/-) mice demonstrated a significant attenuation of HFD-induced visceral fat depot expansion compared to wild type littermate controls. Importantly, unlike other Id proteins, loss of Id3 did not affect adipose depot size in young mice fed chow diet or differentiation of adipocytes in vitro or in vivo. Contrast enhanced ultrasound revealed a significant attenuation of visceral fat microvascular blood volume in HFD-fed mice null for Id3 compared to wild type controls. HFD induced Id3 and VEGFA expression in the visceral stromal vascular fraction and Id3(-/-) mice had significantly lower levels of VEGFA protein in visceral adipose tissue compared to wild type. Furthermore, HFD-induced VEGFA expression in visceral adipose tissue was completely abolished by loss of Id3. Consistent with this effect, Id3 abolished E12-mediated repression of VEGFA promoter activity. CONCLUSIONS: Results identify Id3 as an important regulator of HFD-induced visceral adipose VEGFA expression, microvascular blood volume, and depot expansion. Inhibition of Id3 may have potential as a therapeutic strategy to limit visceral adiposity.

Involvement of the brachial plexus and its branches by cystic hygromas.

Lymphatic malformations that involve the nervous system are uncommon. The authors review their experience with involvement of the brachial plexus and its branches by cystic hygromas. A retrospective review of the authors' experience with pathology of the pediatric brachial plexus revealed 4 cases involving patients with compression of this structure and its branches due to cystic hygroma. Although such cases are apparently rare, the neurosurgeon should consider malformations of the lymphatic system in the differential diagnosis of masses involving the brachial plexus and its branches.

Chronic emesis due to compression of the area postrema by the posterior inferior cerebellar artery: resolution following microvascular decompression.

Chronic emesis may result from a variety of causes. To the authors' knowledge, compression of the area postrema by regional vessels resulting in chronic emesis has not been reported. The authors report on a child who presented with chronic medically intractable emesis and significant weight loss requiring jejunostomy feeding. Surgical exploration of the posterior cranial fossa found unilateral compression of the area postrema by the posterior inferior cerebellar artery. Microvascular decompression resulted in postoperative and long-term resolution of the patient's emesis. Although apparently very rare, irritation of the area postrema from the posterior inferior cerebellar artery with resultant medically intractable chronic emesis may occur. Therefore, the clinician should be aware of this potential etiology when dealing with such patients.